Arginine-vasopressin (AVP) is a peptide consisting of 9 amino acids which is synthesized predominantly in the hypothalamus, and is deeply involved as a posterior pituitary hormone in the regulation of blood plasma osmotic pressure, blood pressure and amount of body fluid.
To date, three subtypes of AVP receptor have been cloned, V1a, V1b and V2 receptors, and all are known to be seven times membrane receptors. The V2 receptor is coupled to Gs to increase the amount of cAMP. The V1a receptor is coupled to Gq/11 to enhance PI response and increase intracellular Ca. The V1a receptor is expressed in brain, liver, adrenal gland, vascular smooth muscle and the like, and is involved in vasoconstriction action. On the other hand, like V1a receptor, the V1b receptor is also coupled to the Gq/11 to enhance PI response (Non-patent Reference 1/Non-patent Reference 2). The V1b receptor is present mostly in the pituitary gland (expressed in 90% or more of ACTH secreting cells of the anterior lobe), and is postulated to participate in the ACTH secretion from the anterior pituitary gland by AVP. The V1b receptor is also present in a broad region of the brain other than the pituitary gland, and is present in large amounts in limbic systems such as hippocampus, amygdala and entorhinal cortex, and the cerebral cortices, olfactory bulb, raphe nuclei which are origion of serotonin nervous (Non-patent Reference 3/Non-patent Reference 4).
Recently, a relationship between the V1b receptor and depression and anxiety disorders has been suggested, and on the usefulness of a V1b receptor antagonist have been investigated. In V1b receptor KO mouse, aggressive behavior was shown to decrease (Non-patent Reference 5). In addition, an increase in time spent in the open arm (anxiolytic-like effect) by injection of a V1b receptor antagonist in the septal region was reported in an elevated plus-maze test (Non-patent Reference 6). Recently, a V1b receptor specific antagonist was discovered, which is a 1,3-dihydro-2H-indol-2-one compound that can be administered peripherally (Patent References 1 to 7). In addition, antidepressant and anxiolytic effects of 1,3-dihydro-2H-indol-2-one compound, have been reported in a variety of animal models (Non-patent Reference 7/Non-patent Reference 8). The compound disclosed in Patent Reference 1 is a compound that has a high affinity (1×10−9 mol/L to 4×10−9 mol/L) for and acts selectively on the V1b receptor, and this compound antagonizes AVP, AVP+CRF or restraint stress-induced ACTH increase.
In addition, compound with a fluorine atom-substituted alkoxy group introduced on the benzene sulfonyl moiety linked at position 1 of 1,3-dihydro-2H-indol-2-one, compound with three substituents introduced on the benzene sulfonyl moiety, and pyrrolidin-2-one compound fused with a heteroaromatic ring an the like are not disclosed in Patent References 1 to 7.